(a) Field of the Invention
The present invention relates to biodegradable and bioabsorbable block copolymers in solid powder or powder wax form that can be easily formed into an aqueous polymer solution and exhibit reverse thermal gellation properties upon exposure to elevated temperatures, such as upon exposure to body temperature just prior to or upon administration. The disclosed polymers are advantageously used, for example, in the parenteral administration of drugs.
(b) Description of the Related Art
Biodegradable block copolymers exhibiting reverse thermal gellation are disclosed in U.S. Pat. Nos. 6,201,072; 6,117,949; and 6,004,573 to Rathi et al. and U.S. Pat. No. 5,702,717 to Cha et al. These polymer compositions exist as a liquid solution at low temperatures, then reversibly form gels at physiologically relevant temperatures, and provide good drug release characteristics. These compositions include biodegradable ABA- or BAB-type block copolymers having an average molecular weight of between about 2000 and 4990, and include about 51 to 83% by weight of an hydrophobic A polymer block comprising a biodegradable polyester and about 17 to 49% by weight of a hydrophilic B polymer block comprised of polyethylene glycol. U.S. Pat. Nos. 7,018,645 and 7,135,190 to Piao et al., disclose mixtures of triblock copolymers exhibiting similar reverse thermal gellation properties.
These polymeric drug delivery polymers exhibit reverse thermal gellation properties, but have been found to be especially difficult to form or reconstitute into aqueous drug delivery compositions. The difficulty in reconstituting these compositions has necessitated performing the reconstitution step in a manufacturing facility to produce an aqueous drug delivery product. After reconstitution, these aqueous drug delivery products exhibiting reverse thermal gellation would typically be stored in the form of frozen aqueous polymer solution up to the point of use. At room temperature, aqueous polymer solutions of these reverse thermal gellation polymers would begin to degrade. Therefore, these aqueous drug delivery compositions would need to be shipped and stored in a refrigerated or frozen state. Previously known reverse thermal gellation drug delivery compositions, such as those disclosed by Rathi et al., exhibit good stability if stored and shipped in frozen form. For drug delivery applications, the polymers disclosed by Rathi et al. can be stored and shipped in ready-to-inject prefilled syringes or product vial configurations (single or double vial). The syringes and vials are thawed prior to injection, which takes between 24 and 48 hours.
Other ABA triblock copolymers have incorporated caprolactone and glycolic acid into the hydrophobic blocks with a single hydrophilic polymers. See Chinese Published Application No. CN 1958074 A. However, the synthetic methods disclosed therein are inadequate to produce a triblock copolymer composition having a desirable molecular weight and polymer properties. For example, the synthetic methods disclosed therein rely on the use of a commercially available polyethylene glycol monomer of a nominal molecular weight (i.e., 1540 Daltons). Although polyethylene glycol having specific nominal molecular weights other than 1540 are available, it has been found that triblocks made from a single polyethylene glycol component with a single average molecular weight lack the most desirable combination of reconstitution, drug release, swelling and dissolution characteristics for the range of drugs utilized and in the indications essential for controlled release systems.
The present inventors have found that the drug release, degradation, swelling and dissolution characteristics depend significantly on the composition of the thermoreversible block copolymer. Specifically, it has been found that precise control of the hydrophilic polymer length as well as the hydrophobic polymer composition is critical to obtaining a desirable reconstitution, drug release, swelling and dissolution characteristics. Prior block copolymers exhibiting reverse thermal gellation properties have been found to have inadequate reconstitution, drug release, swelling, and/or dissolution characteristics. Accordingly, there is a need in the art for an aqueous biodegradable polymeric drug delivery composition exhibiting reverse thermal gellation that can be stored at room temperature and easily formed or reconstituted at the point of use in a minimal amount of time having desirable drug release, swelling and dissolution characteristics.